Half-Life Elimination

Protein Binding

75% to 80% bound to serum proteins (Gwilt 1998)

Special Populations: Renal Function Impairment

Because renal excretion is a pathway of elimination for hydroxyurea, consider dosage reduction in patients with renal impairment. Mean AUC was 64% higher in patients with CrCl <60 mL/minute than in patients with healthy renal function.

Sickle cell anemia (Droxia): Management of sickle cell anemia (to reduce the frequency of painful crises and to reduce the need for blood transfusions in patients with recurrent moderate to severe painful crises)

Off Label Uses

Acute myeloid leukemia, cytoreduction

Data from a nonrandomized, open-label trial in adults with acute myeloid leukemia (AML) suggest that hydroxyurea may be beneficial for cytoreduction in patients with AML [Grund 1977]. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Based on the European LeukemiaNET panel recommendations, hydroxyurea is effective and recommended for cytoreduction in AML [European LeukemiaNET [Dohner 2010]].

Essential thrombocythemia, high-risk

Data from an open-label, randomized trial in patients with essential thrombocythemia at high risk for vascular events supports the use of hydroxyurea (in combination with low-dose aspirin) for the management of this condition [Harrison 2005].

Head and neck cancer (with concurrent radiation therapy and fluorouracil)

Data from a phase II randomized trial in patients with advanced squamous carcinoma of the head and neck supports the use of hydroxyurea in the treatment of this condition [Garden 2004].

Hypereosinophilic syndrome

Data from a nonrandomized, retrospective study evaluating multiple therapies in patients with hypereosinophilic syndrome supports the use of hydroxyurea in the treatment of patients with this condition [Parillo 1978]. Clinical experience also suggests the utility of hydroxyurea in the treatment of hypereosinophilic syndrome [Klion 2006]. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Meningioma

Data from 2 open-label, nonrandomized trials in patients with recurrent or high risk meningioma or those with an unresectable or residual meningioma suggest that hydroxyurea may be beneficial for the treatment of this condition [Newton 2000], [Rosenthal 2002]. Additional data may be necessary to further define the role of hydroxyurea in this condition.

Polycythemia vera, high-risk

Data from a randomized trial in patients with polycythemia vera supports the use of hydroxyurea in the treatment of patients with this condition [Najean 1997]. Clinical experience also suggests the utility of hydroxyurea in the treatment of patients with polycythemia vera [Finazzi 2007]. Additional trials may be necessary to further define the role of hydroxyurea in the treatment of this condition.

Contraindications

US labeling: Hypersensitivity to hydroxyurea or any component of the formulation

Dosing: Adult

Note: Doses should be based on ideal or actual body weight, whichever is less (per manufacturer). Prophylactic administration of folic acid is recommended.

US labeling:

Chronic myeloid leukemia (CML), head and neck cancer: Oral: Initial: 15 mg/kg/day; individualize treatment based on tumor type, disease state, response to treatment, patient risk factors, and current clinical practice standards. May be used alone or in combination with other agents or radiation.

Sickle cell anemia: Oral:

Manufacturer’s labeling: Initial: 15 mg/kg/day as a single dose; if blood counts are in an acceptable range, may increase by 5 mg/kg/day every 12 weeks until the maximum tolerated dose of 35 mg/kg/day is achieved or the dose that does not produce toxic effects over 24 consecutive weeks (do not increase dose if blood counts are between acceptable and toxic ranges). Monitor for toxicity every 2 weeks; if toxicity occurs, withhold treatment until the bone marrow recovers, then restart with a dose reduction of 2.5 mg/kg/day; if no toxicity occurs over the next 12 weeks, then the subsequent dose may be increased by 2.5 mg/kg/day every 12 weeks to a maximum tolerated dose (dose which does not produce hematologic toxicity for 24 consecutive weeks). If hematologic toxicity recurs a second time at a specific dose, discontinue treatment.

Alternate recommendations (off-label dose): Initial: 15 mg/kg/day; if dosage escalation is warranted based on clinical/laboratory findings, may increase by 5 mg/kg/day increments every 8 weeks. Monitor for toxicity at least every 4 weeks when adjusting dose; aim for a target absolute neutrophils ≥2,000/mm3 (younger patients with lower baseline counts may safely tolerate absolute neutrophils down to 1,250/mm3; maintain platelet count ≥80,000/mm3. Give until mild myelosuppression is achieved (absolute neutrophils: 2,000/mm3 to 4,000/mm3), up to a maximum dose of 35 mg/kg/day. If toxicity occurs (neutropenia or thrombocytopenia), withhold treatment until the bone marrow recovers (monitor weekly), then restart at a dose 5mg/kg/day lower than the dose given prior to onset of cytopenias (NHLBI 2014). Note: A clinical response to treatment may take 3 to 6 months; a 6 month trial on the maximum tolerated dose is recommended prior to considering discontinuation due to treatment failure; effectiveness of hydroxyurea depends upon daily dosing adherence. For patients who have a clinical response, long-term hydroxyurea therapy is indicated (NHLBI 2014)

Canadian labeling:

Note: Titrate dose to patient response; if WBC count falls to <2,500/mm3, or the platelet count to <100,000/mm3, therapy should be interrupted for at least 3 days and resumed when values rise toward normal.

Manufacturer’s labeling: Neutrophils <2,000/mm3, platelets <80,000/mm3, hemoglobin <4.5 g/dL, or reticulocytes <80,000/mm3 with hemoglobin <9 g/dL: Interrupt treatment; following recovery, may resume with a dose reduction of 2.5 mg/kg/day. Hydroxyurea may then be titrated up or down every 12 weeks in 2.5 mg/kg/day increments until the patient is at a stable dosage that does not result in hematologic toxicity for 24 weeks. If hematologic toxicity recurs a second time at a specific dose, discontinue treatment.

Dosing: Obesity

ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer (solid tumors): Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs 2012). Note: The manufacturer recommends dosing based on ideal or actual body weight, whichever is less.

Extemporaneously Prepared

100 mg/mL Oral Solution (ASHP Standard Concentration) (ASHP 2017)

A 100 mg/mL oral solution may be prepared with capsules. Mix the contents of twenty 500 mg capsules with enough room temperature sterile water (~50 mL) to initially result in a 200 mg/mL concentration. Stir vigorously using a magnetic stirrer for several hours, then filter to remove insoluble contents. Add 50 mL Syrpalta (flavored syrup without color, HUMCO) to filtered solution, resulting in 100 mL of a 100 mg/mL hydroxyurea solution. Stable for 1 month at room temperature in amber plastic bottle (Heeney 2004).

Administration

Administer at the same time each day.

Impervious gloves should be worn when handling bottles containing hydroxyurea or when handling/administering intact capsules (single gloves are recommended for administration of intact capsules). Wash hands with soap and water before and after contact with the bottle or capsules when handling. Avoid exposure to crushed or open capsules. If skin contact with crushed or opened capsules occurs, immediately wash the affected area thoroughly with soap and water. If eye(s) contact with crushed or opened capsules occurs, the affected area should be flushed thoroughly with water or isotonic eyewash designated for that purpose for at least 15 minutes. If the powder from the capsule is spilled, immediately wipe it up with a damp disposable towel and discard (along with the empty capsules) in a closed container, such as a plastic bag. The spill areas should then be cleaned 3 times using a detergent solution followed by clean water.

Dietary Considerations

Supplemental administration of folic acid is recommended; hydroxyurea may mask development of folic acid deficiency.

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Test Interactions

False-negative triglyceride measurement by a glycerol oxidase method. An analytical interference between hydroxyurea and enzymes (lactate dehydrogenase, urease, and uricase) may result in false elevations of lactic acid, urea, and uric acid.

Warnings/Precautions

Concerns related to adverse effects:

• Bone marrow suppression: [US Boxed Warning]: Hydroxyurea may cause severe myelosuppression. Monitor blood counts at baseline and throughout treatment. Interrupt treatment and reduce dose as necessary. Leukopenia and neutropenia commonly occur (thrombocytopenia and anemia are less common); leukopenia/neutropenia occur first. Severe or life-threatening myelosuppression may occur at the recommended dose. Hematologic toxicity is reversible (rapid) with treatment interruption. Use with caution in patients with a history of prior chemotherapy or radiation therapy; myelosuppression is more common. Correct severe anemia prior to initiating treatment. Do not initiate therapy if bone marrow function is markedly reduced. Hydroxyurea should not be used in sickle cell anemia with severe bone marrow suppression (neutrophils <2000/mm3, platelets <80,000/mm3, hemoglobin <4.5 g/dL, or reticulocytes <80,000/mm3 when hemoglobin <9 g/dL per the manufacturer’s labeling).

• Cutaneous vasculitic toxicities: Vasculitic ulcerations and gangrene have been reported with hydroxyurea treatment, most often in patients with a history of or receiving concurrent interferon therapy; discontinue hydroxyurea and consider alternate cytoreductive therapy if cutaneous vasculitic toxicity develops.

• Erythrocyte abnormalities: Self-limiting macrocytosis/megaloblastic erythropoiesis may be seen early in treatment (may resemble pernicious anemia, but is unrelated to vitamin B12 or folic acid deficiency). Plasma iron clearance may be delayed and iron utilization rate (by erythrocytes) may be reduced. Prophylactic folic acid supplementation is recommended.

• Secondary malignancy: [US Boxed Warning]: Hydroxyurea is carcinogenic. Advise sun protection and monitor patients for malignancies. Treatment of myeloproliferative disorders (eg, polycythemia vera, thrombocythemia) with long-term hydroxyurea is associated with secondary leukemia; it is unknown if this is drug-related or disease-related. Skin cancer has been reported with long-term hydroxyurea use. Monitor for signs/symptoms of secondary malignancies.

• Elderly: May be more sensitive to the effects of hydroxyurea; may require lower doses.

• Radiation therapy recipients: Patients with a history of radiation therapy are at risk for exacerbation of post irradiation erythema and myelosuppression.

Special handling:

• Hazardous agent: To decrease risk of exposure, wear gloves when handling and wash hands before and after contact.

Other warnings/precautions:

• Immunizations: Avoid use of live vaccines during hydroxyurea therapy. Concomitant use may potentiate viral replication and may possibly increase vaccine adverse reactions due to suppression of normal defense mechanisms by hydroxyurea; the antibody response to vaccines may be decreased. Immunization with live vaccines may result in severe infection. Consider consultation with a specialist if immunization with a live vaccine is necessary.

Pregnancy Considerations

Adverse effects have been observed in animal reproduction studies. Based on its mechanism of action, hydroxyurea may cause fetal harm if administered during pregnancy. Women of reproductive potential should be advised to avoid becoming pregnant during treatment (verify pregnancy status prior to starting hydroxyurea therapy) and should use effective contraception during and for at least 6 months after completion of therapy. Hydroxyurea use may damage spermatozoa and testicular tissue; males with female partners of reproductive potential should use effective contraception during and for at least 1 year after therapy. Azoospermia or oligospermia (sometimes reversible) has been observed in male patients; counsel males of reproductive potential about sperm banking prior to therapy initiation.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.